Successful therapy with a pharmaceutical agent requires that the agent satisfy numerous requirements imposed by the physiology of the host and of the disease or condition. The requirements include: (i) adequate ability to interact with the target receptor(s); (ii) appropriate physical properties for presence at the location of the receptors in concentrations that permit the interactions noted above; (iii) appropriate physical properties to allow the agent to enter the body and distribute to the location of the receptors by any means; (iv) sufficient stability in fluids of the body; (v) the absence of toxic effects in compartments where the therapeutic agent is most concentrated, or in any other compartment where the therapeutic agent is located; and (vi) the absence of sequestration into non-physiological compartments and so on.
In general, these compounding requirements limit the nature of pharmaceutical compounds that have utility in vivo and thus reduce the probability of discovering adequately active molecules from de novo starting points. In response to these constraints, significant effort has been applied to the question of predicting ideal physical properties for pharmaceutical molecules. Authors such as Lipinski (Lipinski et al., 2001) have described rules of therapeutic agent design which, amongst other parameters, predicts that ideal therapeutic agents will have few functions such as hydroxy groups, a molecular weight below 500 Da, mild basicity, and moderate lipophilicity (log P<5) (Lipinski et al., 2001). Unfortunately, these parameters are too general to inform the direct synthesis of highly bioavailable compounds. Furthermore, these requirements are not helpful for larger molecule chemistry (MW>500) such as the compounds disclosed here.
Recently, improvements in the technology of synthetic chemistry and molecular biology have allowed the testing of large numbers of molecules and the discovery of many ligands with adequate affinity to their targets to have some potential in vivo. Many such molecules prove inadequate on in vivo testing largely due to the manifold, stringent, and often conflicting (i.e. stability without toxicity) requirements outlined above.
In addition to the difficulties facing many new molecules, many existing molecules in clinical use also exhibit inadequate properties of uptake, distribution, stability and toxicity (Lipinski et al. 2001). These observations demonstrate, that in general, deficiencies in uptake, distribution, and stability result in inadequate therapy from existing molecules and inadequate and uneconomical probabilities of success in the discovery of new molecules.
Such problems often fall within the scope of therapeutic agent delivery—a discipline which combines many aspects of formulation with techniques for introducing the agent into the host body. Delivery methods are frequently designed to permit passage through a single barrier (i.e. the skin) (WO 01/13957) or the intestine (WO 01/20331) after which the agent must again conform with the general requirements above in order to act at the in vivo target. Certain delivery strategies involve a physical preparation such as liposomes (Debs et al. 1990; Jaafari, Foldvari, 2002) or anti-body conjugates (Everts et al., 2002) which further direct the molecules within the host body. Others rely on the addition of cationic lipids to formulations, the use of transport proteins as a route of uptake (WO 01/20331). The use of transport processes deliberately in therapeutic agent design is perhaps best illustrated by the nucleoside therapeutic agents, which to varying degrees, are taken up as metabolites and whose transport to mitochondria is a major cause of toxicity (WO 98/29437) For example, see European Patent No. 0009944B1, European Patent No. 0044090A3, and Japanese Patent No. 05163293. Such methods may enhance performance in therapy or reduce toxicity but they increase cost and require direct introduction into the blood stream which is impractical in chronic use.
More preferable would be small molecules that possess the appropriate structures and properties to mediate efficient uptake and stability. Such small molecules would ideally be able to carry a range of therapeutic agents of varying properties such that they could be commercialized in more than one indication. However, there is a requirement that they be inactive and stable enough to ensure that the cargo molecule is carried in the periphery (Harada et al. 2000).
The present invention represents a significant advance in that it provides for a means of improving the bioavailability and efficacy of a variety of molecules in vivo using a series of rational and facile assays to select desirable compounds based on known pharmacophores or pharmaceutical lead structures that have not been optimized for in vivo action.